Hypoglycaemically and hypolipidaemically active derivatives of phenylacetic acid

ABSTRACT

Phenylacetic acid derivatives of the formula ##STR1## wherein A is an aryl radical optionally substituted by halogen, trifluoromethyl, alkyl, alkoxy, alkenyloxy, alkoxyalkoxy, alkyl-substituted amino or aryloxy, or a heterocyclic ring system optionally substituted by halogen, alkyl or alkoxy, 
     Y is a valency bond or an optionally branched alkylene radical containing up to 3 carbon atoms, and 
     R 1  and R 2  each independently is hydrogen or a lower alkyl radical, 
     or a physiologically compatible salt or ester thereof, exhibit marked hypoglycaemic and hypolipidaemic activity.

This is a division of application Ser. No. 701,717, filed July 1, 1976now U.S. Pat. No. 4,207,341.

The present invention relates to the preparation of hypoglycaemicallyand hypolipidaemically active phenylacetic acid derivatives.

The phenylacetic acid derivatives according to the present invention arecompounds of the general formula ##STR2## wherein A is an aryl radicaloptionally substituted by halogen, trifluoromethyl, alkyl, alkoxy,alkenyloxy, alkoxyalkoxy, alkyl-substituted amino or aryloxy, or aheterocyclic ring system optionally substituted by halogen, alkyl oralkoxy,

Y is a valency bond or an optionally branched alkylene radicalcontaining up to 3 carbon atoms, and

R₁ and R₂ each independently is hydrogen or a lower alkyl radical,

or a physiologically compatible salt or ester thereof.

By alkyl and alkenyl, there are to be understood, in all cases, radicalswith up to 5 and preferably up to 3 carbon atoms. The alkyl radical ispreferably a methyl radical and the alkoxy radical is preferably amethoxy to pentyloxy radical. Alkyl-substituted amino is preferably adimethylamino radical. The alkenyloxy radical is preferably an allyloxyradical, the aryloxy radical is preferably a phenoxy radical and thealkoxyalkoxy radical is a radical with 2 to 5 carbon atoms and isespecially a methoxyethoxy radical. The aryl radical is to be understoodto be an aromatic radical containing 6 to 10 carbon atoms and ispreferably a naphthyl or phenyl radical.

The optionally substituted heterocyclic ring system is preferably athienyl, pyridyl, pyrazinyl, chromanyl, quinolyl, indolyl or optionallyhydrogenated benzofuranyl radical.

Halogen is to be understood to mean preferably fluorine, chlorine orbromine.

The new compounds of general formula (I) according to the presentinvention and the physiologically compatible salts and esters thereofpossess surprisingly outstanding hypoglycaemic and/or hypolipidaemiceffects.

The new compounds according to the present invention can be prepared,for example, by one of the following methods:

(a) reaction of an amine of the general formula ##STR3## wherein Y, R₁and R₂ have the same meanings as above an acid derivative thereof with areactive derivative an acid of the general formula A--COOH, wherein Ahas same meaning as above; or

(b) oxidation of a compound of the general formula ##STR4## wherein A,Y, R₁ and R₂ have the same meanings as above and B is a residue whichcan be oxidatively converted into a carboxyl group; or

(c) reduction of a compound of the general formula ##STR5## wherein Aand Y have the same meanings as above, R' is a hydrogen atom or an alkylradical containing up to 4 carbon atoms and G is a ##STR6## group, inwhich R₁ has the same meaning as above and L is a halogen atom or ahydroxyl group; or

(d) for the case in which R₂ in general formula (I) represents ahydrogen atom, reaction of a ketone of the general formula: ##STR7## inwhich A and Y have the same meanings as above, under the conditions of apossibly modified Willgerodt-Kindler synthesis; or

(e) for the case in which R₁ and R₂ in general formula (I) representhydrogen atoms, reaction of a derivative of a carboxylic acid of thegeneral formula: ##STR8## wherein A and Y have the same meanings asabove, with diazomethane according to the Arndt-Eistert method; or

(f) reaction of a compound of the general formula: ##STR9## wherein Aand Y have the same meanings as above, under the conditions of aFriedel-Crafts reaction, with a compound of the general formula:##STR10## wherein R₁, R₂ and R' have the same meanings as above and Halis a halogen atom; or, for the case in which R₁ and R₂ in generalformula (I) each represent a methyl radical, reaction with an acrylicacid derivative of the general formula: ##STR11## wherein R' has thesame meaning as above; whereafter an acid derivative obtained of generalformula (I) is, if desired, converted into the free acid or a free acidobtained of general formula (I) is, if desired, esterified or, ifdesired, a free acid of general formula (I) is converted into aphysiologically compatible acid-addition salt and, when R₁ and/or R₂ isa hydrogen atom, the product obtained is, if desired, subsequentlyalkylated.

In the case of process (a), as reactive derivatives of the acid A.COOH,there is preferably used an acid chloride which can be obtained in theusual manner, for example, by reaction of the carboxylic acid withthionyl chloride. However, the esters, azides, anhydrides or mixedanhydrides can be used just as well. The reaction with the compound ofgeneral formula (II) can be carried out according to theSchotten-Baumann method. If it is desired to work under anhydrousconditions, then it is preferable to use anhydrous pyridine or someother organic solvent, preferably toluene, acetone or dioxane with anaddition of a tertiary amine, for example triethylamine. Instead of thefree amino compound, the salts thereof can also be employed.

As acid derivatives of the compounds of general formula (II), there arepreferably used the esters, especially the methyl and ethyl esters,nitriles, acid amides and acid anhydrides which then, after the reactionhas taken place, can, if necessary, be converted by hydrolysis in knownmanner into the free carboxylic acids.

The compounds of general formula (II) are new and can be prepared, forexample, by hydrolysis of a compound of the general formula: ##STR12##wherein Y, R₁ and R₂ have the same meanings as above, V is an aryl,lower alkyl or alkoxy radical and X is a residue which can be convertedinto a carboxylic acid group by saponification.

Compounds of the general formula (II), in which R₁ is a hydrogen atom,can also be obtained by saponifying and decarboxylating a compound ofthe general formula: ##STR13## wherein V, Y, R₂, R' and X have the samemeanings as above.

The oxidizable group B in compounds of general formula (III) ispreferably a hydroxymethyl, aminomethyl or formyl radical and, when R₁and/or R₂ is an alkyl radical, can also be an acetyl radical, or afunctional derivative thereof, which can easily be oxidized to acarboxyl group with a conventional oxidation agent, for example, apermanganate or dichromate, in the case of the formyl group also withatmospheric oxygen or silver oxide and in the case of the acetyl radicalalso by means of sodium hypobromite.

The compounds of general formula (III), which are used as startingmaterials in process (b), are also new. Furthermore, the compounds ofgeneral formula (III) in which B is a hydroxymethyl or formyl group alsopossess hypoglycaemic and/or hypolipidaemic effectiveness. They can beprepared in kwown manner, especially in a manner analogous to that ofprocess (a), whereby, instead of the acid of the general formula (II),there is used the corresponding compound containing the oxidizable groupB. Of course, the other way round, compounds of general formula (I) orthe acid derivatives thereof, for example, esters, acid halides and acidamides, can also be reduced to give compounds of general formula (III).

The compounds of general formula (IV), in which G is a --CO-- group,employed as starting materials in the case of process (c), can beprepared by the reaction of a compound of general formula (VII) with acompound of the general formula: ##STR14## wherein Hal has the samemeaning as above and R" is a lower alkyl radical, preferably a methyl orethyl radical, under the conditions of a Friedel-Crafts reaction. Theesters thus obtained can be subsequently saponified to the correspondingacids.

The reduction of compounds of general formula (IV), in which G is a--CO-- group, can be carried out in the manner of a Clemmenson reductionor by the Wolff-Kishner method with hydrazine/alkali. However, thereduction is preferably carried out catalytically in the presence ofnoble metals, such as platinum or palladium. In this case, the preferredsolvent is glacial acetic acid to which is added a trace of sulfuric orperchloric acid or a molar amount of hydrochloric acid. The reactiontemperature is from 20° to 60° C. and the pressure used can be from 1 to10 ats.

Compounds of the general formula (IV) in which G is a --CH(OH)-- group,can be prepared, for example, by reduction of the corresponding ketocompounds. The reduction can be carried out catalytically in thepresence of noble metals, for example palladium or platinum. Complexmetal hydrides can also be used as reducing agents, sodium borohydridepreferably being used. In this case, the reaction can be carried out inan alcohol, especially in methanol, or also in an aqueous alkalinemedium. The halogen derivatives can also be prepared from the hydroxycompounds in known manner. The reduction of these halogen derivatives togive compounds of general formula (I) can also be carried out in knownmanner, for example, with nascent or catalytically activated hydrogen.

Compounds of general formula (IV), in which G is a ##STR15## group, canbe prepared by the isonitrile method (cf. Chem. Abs. 68, 68721v/1968),for example from an aryl alkyl ketone; if G is a ##STR16## group, thenthese compounds can be obtained from compounds of general formula (IV),in which G is a ##STR17## group, by dehydration.

The acetophenone derivatives of general formula (V) used in process (d)can easily be obtained by acetylation by the Friedel-Crafts method. Forthe preparation of compounds of general formula (I), in which R₁ and R₂each represent hydrogen atoms, compounds of general formula (V) arereacted, according to the Willgerodt-Kindler synthesis, with sulfur anda secondary amine, preferably morpholine. The thiomorpholide obtained inthe case of the Willgerodt-Kindler synthesis is saponified in knownmanner to give a carboxylic acid of general formula (I).

Instead of sulfur and the secondary amine, for the simultaneousreduction of the carbonyl group to a methylene radical and oxidation ofthe methyl radical to a carboxyl radical, there can also be used thallicsalts, preferably thallic nitrate, and perchloric acid.

For the case in which compounds of general formula (I) are to beprepared in which R₁ is a methyl radical and R₂ is a hydrogen atom, theketone of general formula (V) can be first condensed with rhodanine. Itis subsequently saponified and the α-thiopyruvic acid obtainedconverted, under the conditions of a Willgerodt-Kindler synthesis, intothe thiomorpholide, which is subsequently saponified to give acarboxylic acid.

Process (e) incorporates the Arndt-Eistert method in which a derivative,especially a chloride, of a carboxylic acid of general formula (VI) isconverted by means of diazomethane into a diazoketone. By means of theaction of ultra-violet light, heat or catalysts, for example, silveroxide, the diazoketone is converted into a phenyl acetic acid of generalformula (I).

If compounds of general formula (I) are to be synthesized according toprocess (f), then compounds of general formula (VII) are condensed inthe presence of aluminum chloride with a substituted haloacetic acidester or with a methacrylic acid derivative in an appropriate solvent,for example ethylene chloride, at a reaction temperature of from 0° to80° C.

When it is desired to carry out esterification of carboxylic acids ofgeneral formula (I), there can, in principle, be used all alcohols. Thepreferred alcohols include alkanols containing up to 5 carbon atoms aswell as amino, alkylamino, hydroxy and alkoxy substitution productsthereof containing up to about 5 carbon atoms in the substituent, e.g.the lower monohydroxy alcohols, for example, methanol, ethanol orn-propanol, as well as polyhydroxy alcohols, for example glycol, oralcohols containing other functional groups, for example ethanolamine orglycol ethers.

When it is desired to carry out a subsequent alkylation of compounds ofgeneral formula (I), in which R₁ and/or R₂ each represent hydrogenatoms, then this can be carried out in the usual manner withconventional alkylation agents, for example alkyl halides or dialkylsulfates.

The physiologically compatible salts are, in particular, the alkalimetal, alkaline earth metal and ammonium salts, as well as salts withblood sugar-lowering basic compounds, preferably biguanides. Thepreparation of these salts is carried out in the usual way, for example,by reaction with the corresponding free bases or carbonates.

As blood sugar-lowering and/or anti-hyperlipidaemic compositionsaccording to the present invention, there can be considered all theconventional oral and parenteral forms of administration, for example,tablets, capsules, dragees, syrups, solutions, suspensions, drops,suppositories and the like. For this purpose, the active material ismixed with solid or liquid carrier materials and subsequently broughtinto the desired form. Solid carrier materials include, for example,starch, lactose, mannitol, methyl cellulose, talc, highly dispersedsilicic acid, high molecular weight fatty acids (such as stearic acid),gelatine, agar-agar, calcium phosphate, magnesium stearate, animal andvegetable fats and solid high molecular weight polymers (such aspolyethylene glycols). Compositions suitable for oral administrationcan, if desired, contain flavoring and/or sweetening agents. Asinjection medium, it is preferred to use water which contains theconventional additives for injection solutions, such as stabilizingagents, solubilizing agents and/or buffers. Additives of this typeinclude, for example, acetate and tartrate buffers, ethanol,complex-forming agents (such as ethylenediamine-tetraacetic acid and thenontoxic salts thereof) and high molecular weight polymers (such aspolyethylene oxide) for viscosity regulation.

The following Examples are given for the purpose of illustrating thepresent invention:

EXAMPLE 1 4-(5-Chloro-2-methoxybenzamido)-phenylacetic acid

8.9 g Ethyl 4-aminophenylacetate are suspended in 200 ml. toluene. Afterthe addition of 4 ml pyridine, a solution of 10.2 g5-chloro-2-methoxybenzoyl chloride in 10 ml toluene is added dropwisethereto and the reaction mixture heated under reflux for 2 hours. Aftercooling, the toluene phase is successively shaken out with dilutehydrochloric acid, aqueous sodium bicarbonate solution and water andthereafter dried and evaporated. The evaporation residue is thenrecrystallized twice from ethanol to give 12.2 g (70% of theory) ethyl4-(5-chloro-2-methoxybenzamido)-phenylacetate; m.p. 104° C.

5.2 g of this ethyl ester are heated for 2 hours on a steambath in 80 ml1 N aqueous sodium hydroxide solution. The solution thus obtained isfiltered with charcoal, acidified with hydrochloric acid and theprecipitated 4-(5-chloro-2-methoxybenzamido)-phenylacetic acid isfiltered off and recrystallized from ethanol. The yield is 2.8 g (58%theory); m.p. 199°-201° C.

In an analogous manner, there are obtained, by reaction of ethyl4-aminophenylaceate

(a) with 2-ethoxy-5-chlorobenzoyl chloride, ethyl4-(2-ethoxy-5-chlorobenzamido)-phenylacetate; m.p. 121°-122° C., afterrecrystallization from ethanol; and from this, by saponification,4-(2-ethoxy-5-chlorobenzamido)-phenyl-acetic acid; m.p. 199°-200° C.,after recrystallization from ethanol;

(b) with 2-methoxy-5-methylbenzoyl chloride, ethyl4-(2-methoxy-5-methylbenzamido)-phenylacetate; m.p. 69°-70° C., afterrecrystallization from ethanol; and from this, by saponification,4-(2-methoxy-5-methylbenzamido)-phenylacetic acid; m.p. 140°-142° C.,after recrystallization from ethanol;

(c) with 2-pentyloxy-5-chlorobenzoyl chloride, ethyl4-(2-pentyloxy-5-chlorobenzamido)-phenylacetate, m.p. 69°-71° C. (crudemelting point); and from this, by saponification,4-(2-pentyloxy-5-chlorobenzamido)-phenylacetic acid; m.p. 144° C., afterrecrystallization from ethanol;

(d) with 2-butyloxy-5-chlorobenzoyl chloride, ethyl4-(2-butyloxy-5-chlorobenzamido)-phenylacetate; m.p. 77°-80° C. (crudemelting point); and from this, by saponification,4-(2-butyloxy-5-chlorobenzamido)-phenylacetic acid; m.p. 158° C., afterrecrystallization from ethanol;

(e) with 3,5-dichlorobenzoyl chloride, ethyl4-(3,5-dichlorobenzamido)-phenylacetate; m.p. 152° C. (crude meltingpoint); and from this, by saponification,4-(3,5-dichlorobenzamido)-phenylacetic acid; m.p. 189° C., afterrecrystallization from ethanol-water.

EXAMPLE 2 4-(4-Chlorobenzamido)-phenylacetic acid

7.6 g 4-Aminophenylacetic acid are dissolved in 50 ml 2 N aqueous sodiumhydroxide solution and 50 ml acetone. A solution of 8.8 g4-chlorobenzoyl chloride in 10 ml acetone is added dropwise thereto at0° C. The reaction mixture is further stirred for 3 hours at ambienttemperature, then diluted with water, filtered and the filtrateacidified with dilute hydrochloric acid. The precipitate obtained isreprecipitated via its sodium salt and recrystallized from ethanol.There are obtained 4.2 g (29% of theory)4-(4-chlorobenzamido)-phenylacetic acid; m.p. 252° C.

EXAMPLE 3 4-(5-Chloro-2-methoxybenzamidomethyl)-phenylacetic acid

A solution of 5.0 g 5-chloro-2-methoxybenzoyl chloride in 10 ml acetoneis added, with ice cooling, to a solution of 5.0 g4-aminomethyl-phenylacetic acid hydrochloride in 25 ml 2 N aqueoussodium hydroxide solution and 25 ml acetone. The reaction mixture isthen stirred for 3 hours at ambient temperature, diluted with water,filtered with charcoal and the filtrate acidified with 2 N hydrochloricacid. The precipitate obtained is filtered off with suction and driedand then recrystallized from ethyl acetate/petroleum ether. There isobtained 1.8 g (21% of theory)4-(5-chloro-2-methoxybenzamidomethyl)-phenylacetic acid; m.p. 140°-141°C.

The 4-aminomethylphenylacetic acid hydrochloride (m.p. 220° C.) used asstarting material is obtained by the catalytic hydrogenation of ethyl4-cyanophenylacetate and subsequent saponification with hydrochloricacid.

In an analogous manner, from 4-aminomethylphenylacetic acidhydrochloride and 2-ethoxy-5-chlorobenzoyl chloride, there is obtained4-(2-ethoxy-5-chlorobenzamidomethyl)-phenylacetic acid; m.p. 175° C.,after recrystallization from ethanol.

EXAMPLE 4 4-(2-Butoxy-5-chlorobenzamidomethyl)-phenylacetic acid

11.5 g Ethyl 4-aminomethylphenylacetate hydrochloride (m.p. 172° C.;prepared by the catalytic hydrogenation of ethyl 4-cyanophenylacetate)are suspended in 200 ml toluene. After the addition of 13.9 mltriethylamine, there is added dropwise, while cooling, a solution of12.4 g 2-butoxy-5-chlorobenzoyl chloride in 10 ml toluene. The reactionmixture is subsequently heated under reflux for 2 hours, while stirring.After cooling, the toluene phase is treated successively with dilutehydrochloric acid, aqueous sodium bicarbonate solution and water andthen evaporated. The evaporation residue is heated on a steambath with 2N aqueous sodium hydroxide solution and the solution then filtered. Thefiltrate is acidified with dilute hydrochloric acid. The precipitated4-(2butoxy-5-chlorobenzamidomethyl)-phenylacetic acid is reprecipitatedvia its sodium salt and recrystallized from ethanol. The yield is 3.9 g.(20% of theory); m.p. 198° C.

EXAMPLE 5 4-(2-Benzamidoethyl)-phenylacetic acid

9.6 g 4-(2-Benzamidoethyl)-acetophenone, well mixed with 1.8 g sulfurare suspended in 15 g morpholine and heated under reflux for 18 hours.After cooling, the reaction mixture is dissolved in 50 ml ethanol andfiltered. The filtrate is evaporated and the residue well washed withwater and diethyl ether. The resultant4-(2-benzamidoethyl)-phenylthioacetomorpholide is recrystallized fromdiethyl ether. The yield is 7.1 g (54% of theory); m.p. 130°-132° C.

3.4 g of the thiomorpholide of the substituted phenylacetic acid areboiled for 9 hours in 25 ml ethanol with 1 g potassium hydroxide. Thereaction mixture is then evaporated and the residue stirred with water.The precipitated 4-(2-benzamidoethyl)-phenylacetic acid morpholide isthen filtered off with suction. The yield is 2.8 g (85% of theory); m.p.122°-123° C.

After boiling 2.8 g of the morpholide for 50 hours with 0.8 g sodiumhydroxide and 20 ml ethanol, there is obtained 1.2 g (53% of theory)4-(2-benzamidoethyl)-phenylacetic acid; m.p. 157°-158° C.

EXAMPLE 6 4-[2-Butoxy-5-chlorobenzamido)-ethyl]-phenylacetic acid

To a solution of 12.2 g ethyl 4-(2-aminoethyl)-phenylacetatehydrochloride in 40 ml dioxane and 40 ml. acetone, there is addeddropwise, after the addition of 8 ml pyridine, a solution of 12.3 g2-butoxy-5-chlorobenzoyl chloride in 10 ml acetone. The reaction mixtureis then stirred under reflux for 3 hours and thereafter evaporated in avacuum. The residue is stirred with dilute hydrochloric acid and thenwith aqueous sodium bicarbonate solution, filtered with suction andwashed with water. There are obtained 19 g of crude product which, afterrecrystallization from ethanol, with the addition of small amounts ofwater, gives ethyl4-[2-(2-butoxy-5-chlorobenzamido-ethyl]-phenylacetate; m.p. 80° C.

9.0 g of the crude ethyl ester are heated with 2 N aqueous sodiumhydroxide solution, after the addition of a little ethanol, on asteambath until solution is complete. After distilling off the alcohol,the reaction mixture is filtered with charcoal and the filtrate isfiltered with charcoal and the filtrate is acidified with 2 Nhydrochloric acid. The precipitate obtained is, after drying,recrystallized from ethyl acetate. There are obtained 4.0 g. (47% oftheory) 4-[(2-(2-butoxy-5-chlorobenzamido)-ethyl]-phenylacetic acid;m.p. 131°-132° C.

The ethyl 4-(2-aminoethyl)-phenylacetate hydrochloride used as startingmaterial is prepared in the following manner:4-(2-acetamidoethyl)-acetophenone is reacted with morpholine and sulfurto give the thiomorpholide of 4-(2-acetamidoethyl)-phenylacetic acid(m.p. 117°-118° C.). Subsequent alkaline saponification, followed byesterification with ethanolic hydrochloric acid, gives ethyl4-(2-aminoethyl)-phenylacetate hydrochloride; m.p. 177°-178° C., afterrecrystallization from ethanol.

In an analogous manner, there are obtained, by the reaction of ethyl4-(2-aminoethyl)-phenylacetate hydrochloride:

(a) with 5-chloro-2-methoxybenzoyl chloride, via ethyl4-[2-(5-chloro-2-methoxybenzamido)-ethyl]-phenylacetate (oil),4-[2-(5-chloro-2-methoxybenzamido)-ethyl]-phenylacetic acid; m.p. 127°C., after recrystallization from ethyl acetate;

(b) with 2-ethoxy-5-chlorobenzoyl chloride, via ethyl4-[2-(2-ethoxy-5-chlorobenzamido)-ethyl]-phenylacetate (oil),4-[2-(2-ethoxy-5-chlorobenzamido)-ethyl]-phenylacetic acid; m.p.137°-138° C., after recrystallization from ethanol-water and ethylacetate-petroleum ether;

(c) with 2-allyloxy-5-chlorobenzoyl chloride, via ethyl4-[2-(2-allyloxy-5-chlorobenzamido)-ethyl]-phenylacetate,4-[2-allyloxy-5-chlorobenzamido)-ethyl]-phenylacetic acid; m.p.104°-105° C., after recrystallization from ethyl acetate.

EXAMPLE 7 4-[2-(2-Methoxy-5-methylbenzamido)-ethyl]-phenylacetic acid

3.4 g 2-Methoxy-5-methylbenzoic acid are heated under reflux with 6 mlthionyl chloride for 2 hours. The reaction mixture is then evaporatedand the residue taken up in 15 ml methylene chloride. The solution isadded dropwise to a suspension of 4.8 g ethyl4-(2-aminoethyl)-phenylacetate hydrochloride in 20 ml 2 N aqueous sodiumhydroxide solution, while cooling with ice. By the addition of furtheraqueous sodium hyroxide solution, the pH value of the solution ismaintained at 12. The reaction mixture is then stirred for 1 hour atambient temperature, whereafter the methylene chloride phase isseparated off and shaken out three times with 1 N aqueous sodiumhydroxide solution, dried and evaporated. There are obtained 3.6 g (51%of theory) ethyl 4-[2-(2-methoxy-5-methylbenzamido)-ethyl]-phenylacetatein the form of an oil which is not further purified for the subsequentreaction.

3.6 g of this ethyl4-[2-(2-methoxy-5-methylbenzamido)-ethyl]-phenylacetate are dissolved in30 ml ethanol, 0.8 g sodium hydroxide is added thereto and the reactionmixture is boiled under reflux for 3 hours. It is then evaporated, theresidue is dissolved in water and, after the addition of activecharcoal, is filtered. By the addition of 2 N hydrochloric acid, the4-[2-(2-methoxy-5-methylbenzamido)-ethyl]-phenylacetic acid isprecipitated out. After drying, it is recrystallized from benzene. Theyield is 1.8 g (55% of theory); m.p. 83°-85° C., after recrystallizationfrom benzene.

In an analogous manner, there are obtained, by the reaction of ethyl4-(2-aminoethyl)-phenylacetate hydrochloride

(a) with 5-chloro-2-methyl-2,3-dihydrobenzo[b]furoyl chloride, via ethyl4-[2-(5-chloro-2-methyl-2,3-dihydrobenzo[b]furoyl-(7)-amino)-ethyl]-phenylacetate(oil); 4-[2-(5-chloro-2-methyl-2,3-dihydrobenzo[b]furoyl-(7)-amino)-ethyl]-phenylacetic acid; m.p. 145°-148° C., afterrecrystallization from isopropanol;

(b) with 5-chloro-2-phenoxybenzoyl chloride, via ethyl4-[2-(5-chloro-2-phenoxybenzamido)-ethyl]-phenylacetate (oil),4-[2-(5-chloro-2-phenoxybenzamido)-ethyl]-phenylacetic acid; m.p.132°-135° C., after recrystallization from isopropanol;

(c) with 5-bromo-2-methoxybenzoyl chloride, via ethyl4-[2-(5-bromo-2-methoxybenzamido)-ethyl]-phenylacetate (oil),4-[2-(5-bromo-2-methoxybenzamido)-ethyl]-phenylacetic acid; m.p.148°-150° C., after recrystallization from isopropanol.

EXAMPLE 8 4-[2-(4-Chlorobenzamido)-ethyl]-phenylacetic acid

8.3 g 4-Chlorobenzoyl chloride are added dropwise at 5°-10° C., withinthe course of 10 minutes, to a solution of 11.0 g ethyl4-(2-aminoethyl)-phenylacetate in 90 ml anhydrous pyridine. The reactionmixture is then stirred for 90 minutes at 10° C., subsequently allowedto warm up to 20° C. and thereafter warmed to 40°-45° C. for 30 minutes.The reaction mixture is then cooled and stirred into 900 ml ice water, asolid precipitate thereby being obtained. This is filtered off withsuction and washed with water. There are obtained 14.5 g (94% of theory)of crude product which is recrystallized from isopropanol to give 10.9 g(70% of theory) ethyl 4-[2-(4-chlorobenzamido)-ethyl]-phenylacetate;m.p. 118°-119° C.

13.5 g. ethyl 4-[2-(4-chlorobenzamido)-ethyl]-phenylacetate, dissolvedin 110 ml methanol and 39 ml 2 N aqueous potassium hydroxide solution,are maintained at reflux temperature for 12 hours. The solution is thenevaporated in a vacuum. After dilution with water, it is extracted withdiethyl ether, the aqueous phase is filtered, with the addition ofactive charcoal, and the filtrate is acidified. There are obtained 11.7g (95% of theory) of acid which is recrystallized from 25 ml glacialacetic acid. There are obtained 8.2 g (66% of theory)4-[2-(4-chlorobenzamido)-ethyl]-phenylacetic acid; m.p. 186°-187° C.From the mother liquor, there is obtained a further 1.9 g (15% oftheory) of this acid, which has a melting point of 182°-183° C.

In an analogous mannner, by the reaction of ethyl4-(2-aminoethyl)-phenylacetate with 5-chloro-2-methoxybenzoyl chloride,there is obtained, via ethyl4-[2-(5-chloro-2-methoxybenzamido)-ethyl]-phenylacetate (oil),4-[2-(5-chloro-2-methoxybenzamido)-ethyl]-phenylacetic acid; m.p.127°-128° C., after recrystallization from 75% acetic acid.

EXAMPLE 9 4-[2-(2-Methoxynicotinoylamino)-ethyl]-phenylacetic acid

7.65 g 2-methoxynicotinic acid are suspended in 200 ml tetrahydrofuran,and, after the addition of 22 ml triethylamino, cooled to 0° C. 4.8 mlmethyl chloroformate are added thereto dropwise at 0° C., whilestirring, and stirring is thereafter continued at 0° C. for 30 minutes.12.2 g ethyl 4-(2-aminoethyl)-phenylacetate hydrochloride are now addedportionwise and the reaction mixture thereafter stirred for 1 hour at 0°C. and for 3 hours at ambient temperature. The reaction mixture is thenevaporated in a vacuum and 200 ml. water added thereto. The ester, whichseparates out as an oil, is taken up in ethyl acetate, the ethyl acetatephase is shaken out successively with dilute acetic acid, aqueous sodiumbicarbonate solution and water and, after drying, is evaporated. Theresidue is heated on a steambath in 20 ml 2 N aqueous sodium hydroxidesolution and 50 ml ethanol for 4 hours. After distilling off theethanol, the solution is filtered and acidified with 2 N acetic acid.The precipitated 4-[2-(2-methoxynicotinoylamino)-ethyl]-phenylaceticacid is filtered off with suction and recrystallized from ethanol; theyield is 5.4 g (34% of theory); m.p. 159°-160° C.

In an analogous manner, there is obtained, by the reaction of ethyl4-(2-aminoethyl)-phenylacetate hydrochloride:

(a) with 6-chloroquinoline-8-carboxylic acid, via ethyl4-[2-(6-chloroquinoline-8-carboxamido)-ethyl]-phenylacetate (oil),4-[2-(6-chloroquinoline-8-carboxamido)-ethyl]-phenylacetic acid; m.p.185°-187° C., after recrystallization from ethanol;

(b) with 5-chloro-3-methoxythiophene-2-carboxylic acid, via ethyl4-[2-(5-chloro-3-methoxythenoyl-(2)-amino)-ethyl]-phenylacetate (oil),4-[2-(5-chloro-3-methoxythenoyl-(2)-amino)-ethyl]-phenylacetic acid;m.p. 141° C., after recrystallization from ethyl acetate;

(c) with 5-bromo-2-methoxynicotinic acid, via ethyl4-[2-(5-bromo-2-methoxynicotinoylamino)-ethyl]-phenylacetate (oil),4-[2-(5-bromo-2-methoxynicotinoylamino)-ethyl]-phenylacetic acid; m.p.160°-162° C., after recrystallization from ethanol;

(d) with 6-chlorochromane-8-carboxylic acid, via ethyl4-[2-(6-chlorochromane-8-carboxamido)-ethyl]-phenylacetate (oil),4-[2-(6-chlorochromane-8-carbozamido)-ethyl]-phenylacetic acid; m.p.171°-173° C., after recrystallization from ethanol;

(e) with 5-chloro-2-methoxynicotinic acid, via ethyl4-[2-(5-chloro-2-methoxynicotinoylamino)-ethyl]-phenylacetae (oil),4-[2-(5-chloro-2-methoxynicotinoylamino)-ethyl]-phenylacetic acid; m.p.157°-158° C., after recrystallization from ethanol.

EXAMPLE 10 4-[2-(5-Chloro-2-methoxybenzamido)-ethyl]-phenylacetic acid

3.3 g 4-[2-(5-chloro-2-methoxybenzamido)-ethyl]-acetophenone (m.p.100°-101° C.; prepared by the reaction of 5-chloro-2-methoxybenzoylchloride wih 4-(2-aminoethyl)-acetophenone hydrochloride), are suspendedin 25 ml methanol. After the addition of 5 ml 70% perchloric acid, 3.9 gthallic nitrate trihydrate are added thereto, while stirring. After ashort time, the thallous nitrate formed precipitates out. The reactionmixture is left to stand for 3 days, then filtered with suction and thefiltrate is diluted with water and extracted with chloroform. Afterdrying the chloroform extract over anhydrous sodium acetate, it isfiltered and the filtrate evaporated. The residue obtained is treatedwith 2 N aqueous sodium hydroxide solution. After filtering andacidifying, 4-[2-(5-chloro-2-methoxybenzamido)-ethyl]phenylacetic acidprecipitates out. It is filtered off and recrystallized twice from ethylacetate. The yield is 0.5 g (15% of theory); m.p. 125°-126° C.

EXAMPLE 11 2-{4-[2-Chloro-2-methoxybenzamido)-ethyl]-phenyl}propionicacid

2.5 g 5-Chloro-2-methoxybenzoyl chloride, dissolved in 20 ml methylenechloride, is slowly added, while stirring, to a solution of 3 g ethyl2-[4-(2-aminoethyl)phenyl]-propionate hydrochloride in 12 ml. 1 Naqueous sodium hydroxide solution. The solution is maintained at pH 10by the addition of aqueous sodium hydroxide solution. The reactionmixture is further stirred for 2 hours, the organic phase is thenseparated off, shaken out twice with 2 N aqueous sodium hydroxidesolution and once with 2 N hydrochloric acid and then evaporated. 4 g ofthe oily residue obtained are boiled for 2 hours with 14 ml 2 N aqueoussodium hydroxide solution for the saponification of the ester group.After cooling, the solution is acidified, the desired2-{4-[2-(5-chloro-2-methoxybenzamido)-ethyl]-phenyl}-propionic acidthereby precipitating out. For purification, the product is firstdissolved in an aqueous solution of sodium carbonate, again precipitatedout by the addition of hydrochloric acid and subsequently recrystallizedfrom isopropanol. The yield is 1.9 g (47% of theory); m.p. 143°-144° C.

For the preparation of the ethyl 2-[4-(2-aminoethyl)-phenyl]-propionateused as starting material, ethyl 2-phenylpropionate is chloromethylated,the ethyl 2-(p-chloromethylphenyl)-propionate (b.p. 120°-122° C./0.3 mmHg) thus obtained is reacted with sodium cyanide to give ethyl2-(4-cyanomethylphenyl)-propionate (b.p. 149°-150° C./0.4 mm Hg.) and,by the catalytic hydrogenation of the nitrile group in the presence of apalladium/charcoal catalyst in hydrochloric alcoholic solution, there isobtained the hydrochloride of ethyl2-[4-(2-aminoethyl)-phenyl]-propionate; m.p. 124°-125° C.

EXAMPLE 12 4-[2-(2-Methoxybenzamido)-ethyl]-phenylacetic acid

5.5 g 4-[2-(5-Chloro-2-methoxybenzamido)-ethyl]-phenylglyoxylic acid arehydrogenated in 100 ml glacial acetic acid/0.5 ml perchloric acid in thepresence of 0.5 g palladium/charcoal at 40° C. After completion of thetake up of hydrogen, the reaction mixture is filtered, the filtrate isconcentrated to one half of its original volume, 10 ml concentratedhydrochloric acid are added thereto and the solution then extractedseveral times with methylene chloride. The organic phase is dried andevaporated. The residue is dissolved in 2 N aqueous sodium hydroxidesolution, active charcoal is added thereto, followed by suctionfiltration and the filtrate is mixed with concentrated hydrochloricacid. An oil separates out. After dissolving this oil in hot isopropanoland adding water, the desired4-[2-(2-methoxybenzamido)-ethyl]-phenylacetic acid crystallizes out;yield 3.91 g (80% of theory); m.p. 112°-113° C.

For the preparation of the4-[2-(5-chloro-2-methoxybenzamido)-ethyl]-phenylglyoxylic acid used asstarting material, 10 g4-[2-(5-chloro-2-methoxybenzamido)-ethyl]-acetophenone (cf. Example 10)are suspended in 100 ml water and heated to 70° C. A solution of 16 gpotassium permanganate and 6 g potassium hydroxide in 100 ml water,heated to 70° C., is added thereto in 3 portions. After further stirringthe reaction mixture for 30 minutes at 70° C., it is filtered withsuction while still hot and then acidified. The precipitate obtained isfiltered off and recrystallized from isopropanol. There are obtained 5.5g (49% of theory) of the desired phenylglyoxylic acid derivative; m.p.154°-155° C.

EXAMPLE 13 2-{4-[2-(4-Chlorobenzamido)-ethyl]-phenyl}-2-methylpropionicacid

9.6 g. 4-Chlorobenzoyl chloride are added dropwise to a solution of 14.1g ethyl 2-[4-(2-aminoethyl)-phenyl]-2-methylpropionate hydrochloride in90 ml anhydrous pyridine at 5°-10° C. The reaction mixture is kept at10° C. for 90 minutes, then allowed to warm up to ambient temperatureand subsequently heated to 45° C. for 10 minutes. A part thereof remainsundissolved. The reaction mixture is stirred into 750 ml. ice water,filtered with suction and the filter cake then washed. There areobtained 13.2 g (68% of theory) ethyl2-{4-[2-(4-chlorobenzamido)-ethyl]-phenyl}-2-methylpropionate which,after recrystallization from isopropanol, melts at 108°-109° C.

13.9 g ethyl2-{4-[2-(4-chlorobenzamido)-ethyl]-phenyl}-2-methylpropionate, 100 mlmethanol and 37 ml 2 N aqueous potassium hydroxide solution aremaintained at reflux temperature for 9 hours, the methanol is thendistilled off in a vacuum and the residue is diluted with water andextracted with diethyl ether. The aqueous phase is filtered andacidified. There are obtained 12.8 g (100% of theory) of crude product.After recrystallization from 130 ml glacial acetic acid, there areobtained 12.4 g (94% of theory)2-{4-[2-(4-chlorobenzamido)-ethyl]-phenyl}-2-methylpropionic acid; m.p.234°-235° C.

The ethyl 2-[4-(2-aminoethyl)-phenyl]-2-methylpropionate hydrochloride(m.p. 150°-154° C.) used as starting material is obtained by thereaction of 2-(4-chloromethylphenyl)-2-methylpropionic acid (m.p.121°-122° C.) with sodium cyanide. The2-(4-cyanomethylphenyl)-2-methylpropionic acid obtained melts at105°-106° C. This propionic acid derivative is catalyticallyhydrogenated in ethanolic hydrochloric acid solution to give2-[4-(2-aminoethyl)-phenyl]-2-methylpropionic acid hydrochloride which,after recrystallization from isopropanol, melts at 247°-248° C. Byesterification thereof with ethanol in hydrochloric acid solution, thereis obtained the desired ethyl2-[4-(2-aminoethyl)-phenyl]-2-methylpropionate hydrochloride.

In an analogous manner, by the reaction of ethyl2-[4-(2-aminoethyl)-phenyl]-2-methylpropionate hydrochloride with5-chloro-2-methoxybenzoyl chloride, there is obtained, via ethyl2-{4-[2-(5-chloro-2-methoxybenzamido)-ethyl]-phenyl}-2-methylpropionate(oil),2-{4-[2-(5-chloro-2-methoxybenzamido)-ethyl]-phenyl}-2-methylpropionicacid; m.p. 149°-150° C., after recrystallization from glacial aceticacid.

EXAMPLE 14 4-[2-(5-Chloro-2-methoxybenzamido)-ethyl]-phenylacetic acid

4.0 g Sodium dichromate dihydrate are added to a solution of 3.3 g2-{4-[2-(5-chloro-2-methoxybenzamido)-ethyl]-phenyl}-ethanol in 50 mlglacial acetic acid and the reaction mixture is stirred for 3 days atambient temperature. The glacial acetic acid is distilled off with arotary evaporator, the residue is taken up with water and dilute aqueoussodium hydroxide solution, a small amount of unreacted starting materialis removed by extraction with diethyl ether and, by acidification withhydrochloric acid,4-[2-(5-chloro-2-methoxybenzamido)-ethyl]-phenylacetic acid isprecipitated out. It is filtered off, dried and recrystallized fromethyl acetate; yield 1.8 g (52% of theory); m.p. 124°-126° C.

The 2-{4-[2-(5-chloro-2-methoxybenzamido)-ethyl]-phenyl}-ethanol (oil)used as starting material is obtained by the acylation of2-[4-(2-aminoethyl)-phenyl]-ethanol (oil) with 5-chloro-2-methoxybenzoylchloride in anhydrous methylene chloride in the presence oftriethylamine as acid acceptor.

EXAMPLE 15 2-{4-[2-(Quinoline-8-carboxamido)-ethyl]-phenyl}-propionicacid

6.0 g Quinoline-8-carbonyl chloride (m.p. 156°-160° C.) are added to 6.0g ethyl 2-[4-(2-aminoethyl)-phenyl]-propionate hydrochloride in 50 mlmethylene chloride and a solution of 7 ml triethylamine in 20 mlmethylene chloride slowly added dropwise at 0° C. The reaction mixtureis thereafter stirred for 2 hours at ambient temperature, subsequentlyshaken out 6 times with 2 N aqueous sodium hydroxide solution and twicewith 2 N hydrochloric acid, and the methylene chloride phase is thendried and evaporated. The residue is taken up with diethyl ether,undissolved material is filtered off and the diethyl ether isevaporated. Ethyl2-{4-[2-(quinoline-8-carboxamido)-ethyl]-phenyl}-propionate (oil)remains behind in a yield of 8.0 g (91% of theory). This ester issaponified with 2.0 g sodium hydroxide in 50 ml 80% ethanol by heatingunder reflux for 2 hours. The reaction mixture is thereafter evaporatedto dryness, the residue is taken up in water and diethyl ether, thelayers are separated and the aqueous layer acidified. The2-{4-[2-(quinoline-8-carboxamido)-ethyl]-phenyl}-propionic acid obtainedis again reprecipitated by dissolving in dilute aqueous sodiumbicarbonate solution and acidifying with hydrochloric acid, whereafterit is recrystallized from 50% isopropanol and then from toluene. Theyield is 2.3 g (31% of theory); m.p. 143°-144° C.

In an analogous manner, by the reaction of ethyl4-(2-aminopropyl)-phenylacetate with o-butoxybenzoyl chloride, there isobtained, via ethyl 4-[2-(2-butoxybenzamido)-propyl]-phenylacetate(oil), 4-[2-(2-butoxybenzamido)-propyl]-phenylacetic acid; m.p. 91°-92°C., after recrystallization from isopropanol/water.

The preparation of the ethyl 4-(2-aminopropyl)phenylacetate used asstarting material is carried out in the following manner:4-(2-acetamidopropyl)-acetophenone (m.p. 99°-100° C.) is reacted withmorpholine and sulfur to give the thiomorpholide of4-(2-acetamidopropyl)-phenyl-acid acid (m.p. 147° C.). By boiling with 6N hydrochloric acid, there is obtained 4-(2-aminopropyl)-phenylaceticacid (oily), which is esterified with hydrogen chloride and ethanol. Bytreating the initially formed hydrochloride with dilute aqueous sodiumhydroxide solution, there is obtained the free amino compound in theform of an oil.

EXAMPLE 16 4-[2-(2-Methylquinoline-8-carboxamido)-ethyl]-phenylaceticacid hydrochloride

To 6.5 g 2-methylquinoline-8-carboxylic acid and 8.05 g ethyl4-(2-aminoethyl)-phenylacetate hydrochloride in 120 ml anhydrousmethylene chloride are added at -15° C. first 3.3 ml phosphorousoxychloride and then 14.1 ml triethylamine. The reaction mixture isstirred for 1 hour at -15° C. and for 2 hours at ambient temperature,then extracted twice with 50 ml amounts of 1 N hydrochloric acid,deacidified with aqueous sodium bicarbonate solution and the organicphase completely evaporated. There are obtained 5.4 g of the ethyl esterin the form of an oil which is subsequently saponified for 45 minutes ona water bath with a mixture of 25 ml ethanol and 25 ml 2 N aqueoussodium hydroxide solution. The solution is partially evaporated in arotary evaporator, mixed with water, extracted a few times withmethylene chloride and the aqueous phase is treated with active charcoaland, after the addition of a little isopropanol, acidified withconcentrated hydrochloric acid to a pH of 1. The solution is cooled andthe precipitate is filtered off with suction. There are obtained 4.2 g(31% of theory)4-[2-(2-methylquinoline-8-carboxamido)-ethyl]-phenylacetic acidhydrochloride; m.p. 232°-235° C.

EXAMPLE 17

In a manner analogous to that described in Example 7, there areobtained, by the reaction of ethyl 4-(2-aminoethyl)-phenylacetatehydrochloride

(a) with 5-fluoro-2-methoxybenzoyl chloride, via ethyl4-[2-(5-fluoro-2-methoxybenzamido)-ethyl]-phenylacetate (oil),4-[2-(5-fluoro-2-methoxybenzamido)-ethyl]-phenylacetic acid; m.p.83°-84° C. as the monohydrate, after recrystallization fromethanol/water;

(b) with 3-trifluoromethylbenzoyl chloride, via ethyl4-[2-(3-trifluoromethylbenzamido)-ethyl]-phenylacetate (oil),4-[2-(3-trifluoromethylbenzamido)-ethyl]-phenylacetic acid; m.p.137°-139° C., after recrystallization from ethyl acetate;

(c) with 5-chloroindole-2-carbonyl chloride, via ethyl4-[2-(5-chloroindole-2-carboxamido)-ethyl]-phenylacetate (m.p. 193°-195°C.), 4-[2-(5-chloroindole-2-carboxamido)-ethyl]-phenylacetic acid; m.p.242°-243° C., after recrystallization from ethanol/toluene;

(d) with 5-chloro-2-methylbenzo[b]furoyl chloride, via ethyl4-[2-(5-chloro-2-methylbenzo[b]furoyl-(7)-amino)-ethyl]-phenylacetate(oil),4-[2-(5-chloro-2-methylbenzo[b]furoyl-(7)-amino)-ethyl]-phenylaceticacid; m.p. 166°-168° C., after reprecipitation.

EXAMPLE 18

In a manner analogous to that described in Example 11, by the reactionof ethyl 2-[4-(2-aminoethyl)-phenyl]-propionate hydrochloride with5-chloro-2-(2-methoxyethoxy)-benzoyl chloride (m.p. 49°-51° C.), thereis obtained, via ethyl2-{4-[2-(5-chloro-2-(2-methoxyethoxy)-benzamido)-ethyl]-phenyl}-propionate(oil),2-{4-[2-(5-chloro-2-(2-methoxyethoxy)-benzamido)-ethyl]-phenyl}-propionicacid; m.p. 94°-96° C., after recrystallization from isopropanol/water.

EXAMPLE 19

In a manner analogous to that described in Example 11, there areobtained, by reaction of ethyl 2-[4-(2-aminoethyl)-phenyl]-butyratehydrochloride

(a) with 5-chloropentyloxybenzoyl chloride (b.p. 147°-148° C./0.5 mmHg), via ethyl2-{4-[2-(5-chloro-2-pentyloxybenzamido)-ethyl]-phenyl}-butyrate (oil),2-{4-[2-(5-chloro-2-pentyloxybenzamido)-ethyl]-phenyl}-butyric acid;m.p. 124°-126° C., after recrystallization from 80% isopropanol;

(b) with 5-trifluoromethyl-2-methoxybenzoyl chloride, via ethyl2-{4-[2-(5-trifluoromethyl-2-methoxybenzamido)-ethyl]-phenyl}-butyrate,2-{4-[2-(5-trifluoromethyl-2-methoxybenzamido)-ethyl]-phenyl}-butyricacid; m.p. 133°-136° C., after recrystallization from ethyl acetate.

For the preparation of ethyl 2-[4-(2-aminoethyl)-phenyl]-butyratehydrochloride, ethyl 2-phenylbutyrate is chloromethylated and the ethyl2-(p-chloromethylphenyl)-butyrate obtained (b.p. 117°-123° C./0.2 mm Hg)is reacted with potassium cyanide in acetone to give ethyl2-(p-cyanomethylphenyl)-butyrate (b.p. 156°-160° C./0.3 mm Hg). By thecatalytic hydrogenation of the nitrile group in the presence of apalladium/charcoal catalyst in alcoholic hydrochloric acid solution,there is obtained ethyl 2-[4-(2-aminoethyl)-phenyl]-butyratehydrochloride, which does not crystallize.

EXAMPLE 20 2-{4-[2-(5-Chloro-2-methoxybenzamido)-ethyl]-phenyl}-butyricacid

6.2 g 2-[4-(2-Aminoethyl)-phenyl]-butyric acid hydrochloride aresuspended in 100 ml acetone. After the addition of 50 ml 2 N aqueoussodium hydroxide solution, a solution of 4.8 g 5-chloro-2-methoxybenzoylchloride in 50 ml acetone is added dropwise thereto at ambienttemperature and the reaction mixture then stirred for 2 hours at 50° C.After cooling, the reaction mixture is evaporated in a vacuum and theaqueous solution acidified with dilute hydrochloric acid. The2-{4-[2-(5-chloro-2-methoxybenzamido)-ethyl]-phenyl}-butyric acidobtained solidifies upon triturating with diisopropyl ether and isrecrystallized from diisopropyl ether. The yield is 3.2 g (42.5% oftheory); m.p. 120°-122° C.

The 2-[4-(2-aminoethyl)-phenyl]-butyric acid hydrochloride used asstarting material is prepared in the following manner: 2-phenylbutyricacid is reacted with paraformaldehyde/hydrochloric acid to give2-(4-chloromethylphenyl)-butyric acid (b.p. 173°-176° C./0.1 mm Hg). Bythe reaction thereof with potassium cyanide, there is obtained2-(4-cyanomethylphenyl)-butyric acid (oil) which, after catalytichydrogenation, gives 2-[4-(2-aminoethyl)-phenyl]-butyric acidhydrochloride; m.p. 128°-130° C.

EXAMPLE 21 (1-Phenethylbiguanide)4-[2-(5-chloro-2-methoxybenzamido)-ethyl]-phenylacetate

3.08 g. sodium 4-[2-(5-chloro-2-methoxybenzamido)-ethyl]-phenylacetate(prepared from 4-[2-(5-chloro-2-methoxybenzamido)-ethyl]-phenylaceticacid and the equivalent amount of sodium methylate in methanol) and 2.0g 1-phenethylbiguanide hydrochloride are heated under reflux in 100 mlabsolute ethanol for 1 hour. Thereafter, the reaction mixture isevaporated to one half of its original volume, the precipitated sodiumchloride is filtered off with suction and the filtrate is mixed withdiethyl ether. The desired salt crystallizes out slowly and, forpurification, is dissolved in ethanol and again precipitated out by theaddition of diethyl ether. The salt thus obtained has a melting point of121°-123° C.

EXAMPLE 22

In a manner analogous to that described in Example 11 by the reaction ofethyl 2-[4-(2-aminoethyl)-phenyl]-propionate hydrochloride with3,5-dichloro-2-methoxybenzoylchloride, there is obtained, via ethyl2-{4-[2-(3,5-dichloro-2-methoxy-benzamido)-ethyl]-phenyl}-propionate(oil), sodium2-{4-[2-(3,5-dichloro-2-methoxybenzamido)-ethyl]-phenyl}-propionate;m.p. 238°-240° C.

The hypoglycaemic activity of the test compounds was tested in knownmanner as follows:

The test compounds were administered to male Sprague-Dawley rats with abody weight of 200-220 g by intraperitoneal injection (i.p.) as asolution of the sodium salt or per os (p.o.) as a Tylose suspension.

The test compounds were administered to rabbits either by intravenousinjection (i.v.) into the ear edge vein as a solution of the sodium saltor per os through a stomach tube as a Tylose suspension.

In the following table, there is given the threshold dosage in mg/kg ofbody weight, i.e. the lowest dosage of compound required to produce asignificant reduction in the blood sugar level, viz. about 15-20%.

For purposes of comparison, N₁ -(sulfanilyl)-N₂ -(n-butyl)-urea (soldunder trade name "Nadisan") was tested under the same conditions.

The results are set forth in the following table:

                  TABLE                                                           ______________________________________                                        Active                                                                        material     Threshold dosage (mg/kg)                                         from example Rats          Rabbits                                            ______________________________________                                        1                          100 p.o.                                           1a           100 p.c.       50 p.o.                                           1b                         100 p.o.                                           2                          100 p.o.                                           3                          100 p.o.                                           3a           100 p.o.      100 p.o.                                           6            100 p.o.      100 p.o.                                           6a            50 i.p.       35 i.v., 50 p.o.                                  6b            50 p.o.                                                         6c            25 i.p. (short)                                                                            100 p.o.                                           7             50 i.p.       50 i.v.                                           7a            50 i.p.       25 i.v.                                           7c            25 i.p.       50 i.v.                                           9a           25-50 i.p.    100 p.o.                                           9b           <100 p.o.      50 p.o.                                           9c            25 i.p.       50 p.o.                                           9d                         100 p.o.                                           9e                         100 p.o.                                           11            25 i.p.(short)                                                                              50 i.v. (short)                                   12           100 i.p.                                                         13           100 i.p.                                                         13a           50 i.p.       50 i.v.                                           15            50 i.p.       50 i.v.                                           17a           50 i.p.      100 i.v.                                           17b          100 i.p.      100 i.v.                                           17d           35 i.p.       25 i.v.                                           18           25-50 i.p.     50 i.v. (short)                                   19a           10 i.p.       25 i.v.                                           22           50-100 i.p.   100 i.v.                                           Nadisan*      25 i.p.      200 i.v.                                           ______________________________________                                         *Nadisan = N.sub.1 --(sulfanilyl)--N.sub.2 --(nbutyl)--urea              

The compounds (I) can be administered orally or parenterally in liquidor solid form. As injection medium, it is preferred to use water whichcontains the stabilizing agents, solubilizing agents and/or buffers,conventional for injection solutions. Additives of this type include,for example, tartrate and borate buffers, ethanol, dimethyl sulphoxide,complex-forming agents (such as ethylene diaminetetraacetic acid), highmolecular weight polymers (such as liquid polyethylene oxide) forviscosity regulation or polyoxyethylene derivatives of sorbitananhydrides.

Solid carrier materials include, for example, starch, lactose, mannitol,methyl cellulose, talc, highly dispersed silicic acid, high molecularweight fatty acids (such as stearic acid), gelatine, agar-agar, calciumphosphate, magnesium stearate, animal and vegetable fats and solid highmolecular weight polymers (such as polyethylene glycols). Compositionssuitable for oral administration can, if desired, contain flavoring andsweetening agents.

The material administered may be the acid or a salt or ester thereof. Itis believed that due to hydrolysis in the body the active material is inall these instances the same, viz. probably the acid.

The novel compounds may be administered by themselves or in conjuctionwith carriers which are pharmacologically acceptable, either active orinert. The dosage units are similar to those of the heretofore knownanti-cholesterol agents, e.g., about 0.2 to 2 grams per day for an adultor about 3-30 mg/kg per day although higher or lower dosages can beused. Rather than a single dose it is preferable if the compounds areadministered in the course of a day, i.e., about four applications of100 mg. each at spaced time intervals or 8 of about 50 mg. each. Aconvenient form of administration is in a gelatine capsule.

The dosage of the novel compounds of the present invention for thetreatment of diabetes depends in the main on the age, weight, andcondition of the patient being treated. The preferable form ofadministration is via the oral route in connection with which dosageunits containing 50-500 mg. of active compound in combination with asuitable pharmaceutical diluent is employed. One or two unit dosages aregood from one to four times a day.

For the preparation of pharmaceutical compositions, at least one of thenew compounds (I) is mixed with a solid or liquid pharmaceutical carrieror diluent and optionally with an odoriferous, flavoring and/or coloringmaterial and formed, for example, into tablets or dragees, or with theaddition of appropriate adjuvants, suspended or dissolved in water or anoil, for example, olive oil.

It will be appreciated that the instant specification and examples areset forth by way of illustration and not limitation, and that variousmodifications and changes may be made without departing from the spiritand scope of the present invention.

What is claimed is:
 1. A phenylacetic acid derivative of the formula##STR18## wherein A is a thienyl, pyridyl or quinolyl optionallysubstituted by halogen, lower alkyl or lower alkoxy,Y is a valency bondor an optionally branched alkylene radical containing up to 3 carbonatoms, and R₁ and R₂ each independently is hydrogen or a lower alkylradical,or a physiologically compatible salt thereof.
 2. A compoundaccording to claim 1 wherein such compound is4-[2-(5-bromo-2-methoxy-3-pyridine-carboxyamido)-ethyl]phenylacetic acidof the formula ##STR19## or a physiologically compatible salt thereof.3. A hypoglycaemically active composition of matter comprising ahypoglycaemically effective amount of a compound according to claim 1 ora physiologically compatible salt thereof in admixture with aphysiologically acceptable diluent.
 4. A method of reducing the sugarlevel in the blood which comprises administering to a patient ahypoglycaemically effective amount of a compound according to claim 1 ora physiologically compatible salt thereof.
 5. A hypolipidaemicallyactive composition of matter comprising a hypolipidaemically effectiveamount of a compound according to claim 1 or a physiologicallycompatible salt thereof in admixture with a physiologically acceptablediluent.
 6. A method of reducing the lipid level in the blood whichcomprises administering to a patient a hypolipidaemically effectiveamount of a compound according to claim 1 or a physiologicallycompatible salt thereof.
 7. The method according to claim 6, whereinsaid compound is4-[2-(5-bromo-2-methoxy-3-pyridine-carboxamido)-ethyl]-phenylacetic acidor a physiologically compatible salt thereof.